中国中药杂志

2020, v.45(16) 3945-3951

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华蟾素辅助顺铂化疗对H22肝癌小鼠的抑瘤作用及其相关机制研究
Anti-tumor effect and its related mechanisms of cinobufotalin combined with cisplatin on H22 liver cancer mice

王培培;王永辉;王丽森;吴涛;
WANG Pei-pei;WANG Yong-hui;WANG Li-sen;WU Tao;Clinical Pharmacy Department, Pharmacy Department, Zhumadian Central Hospital;Department of Oncology, Zhumadian Central Hospital;

摘要(Abstract):

为了观察华蟾素对H22肝癌小鼠的抑瘤作用,并探讨其调控机制,取50只昆明小鼠,采用腋窝皮下接种H22腹腔传代细胞建立H22肝癌小鼠模型,随机分为模型组、华蟾素低剂量组、华蟾素高剂量组、顺铂组、顺铂+华蟾素组,分别给予0.01%乙醇溶液、1 mg·kg~(-1)华蟾素、5 mg·kg~(-1)华蟾素、5 mg·kg~(-1)顺铂、5 mg·kg~(-1)顺铂+5 mg·kg~(-1)华蟾素干预10 d。干预期间观察各组小鼠一般状况,并比较各组肿瘤质量、抑瘤率、胸腺指数、组织病理学变化、肿瘤细胞凋亡率及肿瘤组织中磷脂酰肌醇-3激酶(phosphatidylinositol 3-kinase,PI3K)、蛋白激酶B(protein kinase B,Akt)、凋亡相关基因(apoptosis related gene,Fas)、Fas配体(Fas ligand,FasL)mRNA和蛋白及磷酸化Akt(phosphorylated Akt,pAkt)蛋白表达情况。结果表明在建模期间小鼠出现进食量下降、毛色暗淡、精神状态不佳等情况,随时间延长情况逐渐转差;各干预组小鼠精神状态逐渐好转,其中顺铂+华蟾素组改善最为明显。与模型组相比,各干预组肿瘤质量较小(P<0.05);与华蟾素低剂量组相比,华蟾素高剂量组、顺铂组、顺铂+华蟾素组肿瘤质量较小,抑瘤率较高(P<0.05);与华蟾素高剂量组、顺铂组相比,顺铂+华蟾素组肿瘤质量较小,抑瘤率较高(P<0.05)。与模型组相比,华蟾素高剂量组、顺铂+华蟾素组胸腺指数较高,顺铂组较低(P<0.05);与华蟾素低剂量组相比,华蟾素高剂量组胸腺指数较高,顺铂组较低(P<0.05);与华蟾素高剂量组相比,顺铂组胸腺指数较低(P<0.05);与顺铂组相比,顺铂+华蟾素组胸腺指数较高(P<0.05)。病理染色结果显示,模型组肿瘤组织可见大量异质性细胞及核分裂现象,各干预组肿瘤组织内可见细胞碎片、中性粒细胞,呈现弥漫性变性坏死状态,且顺铂+华蟾素组弥漫性坏死现象更为明显。与模型组相比,各干预组肿瘤细胞凋亡率及Fas mRNA和蛋白相对表达量较高,PI3K和FasL mRNA和蛋白相对表达量及pAkt蛋白相对表达量较低(P<0.05);与华蟾素低剂量组相比,华蟾素高剂量组、顺铂组、顺铂+华蟾素组肿瘤细胞凋亡率及Fas mRNA和蛋白相对表达量较高,PI3K和FasL mRNA和蛋白相对表达量及pAkt蛋白相对表达量较低(P<0.05);与华蟾素高剂量组、顺铂组相比,顺铂+华蟾素组肿瘤细胞凋亡率及Fas mRNA和蛋白相对表达量较高,PI3K和FasL mRNA和蛋白相对表达量及pAkt蛋白相对表达量较低(P<0.05)。综上,华蟾素对H22肝癌小鼠有显著抑瘤作用,且能增强小鼠免疫功能、协同增强化疗效果,可能通过调控PI3K/Akt/Fas/FasL信号通路相关基因和蛋白表达发挥作用。
In order to observe the anti-tumor effect of cinobufotalin on H22 liver cancer mice and to explore its regulatory mechanism, 50 Kunming mice were subcutaneously inoculated with H22 intraperitoneal passage cells under the armpit to establish H22 hepatocellular carcinoma model. They were then randomly divided into model group, cinobufotalin low dose group, cinobufotalin high dose group, cisplatin group and cisplatin+cinobufotalin group, which received 0.01% ethanol solution, 1 mg·kg~(-1) cinobufotalin, 5 mg·kg~(-1) cinobufotalin, 5 mg·kg~(-1) cisplatin, 5 mg·kg~(-1)cisplatin + 5 mg·kg~(-1) cinobufotalin respectively for 10 days. The general condition of mice during the intervention was observed, and the inhibition rate, tumor mass, thymus index, histopathological changes of the tumors, apoptotic rate of the tumors, the expressions of phosphatidylinositol 3-kinase(PI3 K), protein kinase B(Akt), apoptosis related gene(Fas), Fas ligand(FasL) mRNA and protein phosphorylated Akt(pAkt) protein in the tumors of each group were compared. The results showed that during the modeling period, the mice showed a decline in food intake, dark fur, poor mental status, and gradually worsened over time. The mental status of mice in each intervention group was improved gradually, especially in the cisplatin+cinobufotalin group. As compared with the model group, the tumor mass of each intervention group was lower(P<0.05). As compared with the cinobufotalin low dose group, the tumor mass was lower and inhibition rate was higher in the cinobufotalin high dose group, cisplatin group and cisplatin+cinobufotalin group(P<0.05). As compared with the cinobufotalin high dose group and the cisplatin group, the tumor mass was lower and the inhibition rate was higher in cisplatin+cinobufotalin group(P<0.05). As compared with the model group, the thymus index was higher in cinobufotalin high dose group and cisplatin + cinobufotalin group, while was lower in cisplatin group(P<0.05). As compared with the cinobufotalin low dose group, the thymus index was higher in the cinobufotalin high dose group and lower in the cisplatin group(P<0.05). As compared with the cinobufotalin high dose group, the thymus index was lower in cisplatin group(P<0.05). As compared with cisplatin group, the thymus index was higher in cisplatin+cinobufotalin group(P<0.05). Pathological staining showed that a large number of heterogeneous cells and mitotic phenomena were observed in the model group. Cell fragments and neutrophils were observed in the tumor tissues of the intervention groups, showing diffuse necrosis, and the diffuse necrosis was more obvious in the cisplatin+cinobufotalin group. As compared with the model group, the apoptotic rate of the tumors and the relative expressions of Fas mRNA and protein were higher in the intervention groups, while the relative expressions of PI3 K, FasL mRNA and protein and the relative expression of pAkt protein were lower in the intervention groups(P<0.05). As compared with the cinobufotalin low dose group, the apoptotic rate of the tumors and relative expression of Fas and protein were higher in the cinobufotalin high dose group, cisplatin group and cisplatin+cinobufotalin group, while the relative expressions of PI3 K, FasL mRNA and protein and pAkt protein were lower(P<0.05). As compared with the cinobufotalin high dose group and the cisplatin group, apoptotic rate of the tumors and the relative expression of Fas mRNA and protein were higher in the cisplatin+cinobufotalin group, while the relative expressions of PI3 K, FasL mRNA and protein and pAkt protein were lower in the cisplatin+cinobufotalin group(P<0.05). In summary, cinobufotalin has significant anti-tumor effect on H22 liver cancer mice, and can enhance the immune function of mice and synergistically enhance the effect of chemotherapy. Its mechanism may be associated with regulating PI3 K/Akt/Fas/FasL signaling pathway related genes and protein expression.

关键词(KeyWords): 华蟾素;肝癌;抑瘤;磷脂酰肌醇-3激酶;蛋白激酶B;凋亡相关基因;Fas配体
cinobufotalin;liver cancer;tumor inhibition;phosphatidylinositol 3-kinase;protein kinase B;apoptosis-related genes;Fas ligand

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基金项目(Foundation): 国家自然科学基金青年基金项目(81501567)

作者(Author): 王培培;王永辉;王丽森;吴涛;
WANG Pei-pei;WANG Yong-hui;WANG Li-sen;WU Tao;Clinical Pharmacy Department, Pharmacy Department, Zhumadian Central Hospital;Department of Oncology, Zhumadian Central Hospital;

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